ABSTRACT OF THE WEEK

Journal of the American Animal Hospital Association
Volume 54 | Issue 4 (2018 Jul/Aug)

Comparison of Compounded, Generic, and Innovator-Formulated Itraconazole in Dogs and Cats.

J Am Anim Hosp Assoc. 2018 Jul/Aug;54(4):195-200.

Janelle Renschler¹, Amanda Albers², Hanna Sinclair-Mackling³, Lawrence Joseph Wheat⁴

¹ From MiraVista Diagnostics, Indianapolis, Indiana.; ² From MiraVista Diagnostics, Indianapolis, Indiana.; ³ From MiraVista Diagnostics, Indianapolis, Indiana.; ⁴ From MiraVista Diagnostics, Indianapolis, Indiana.

Abstract

The triazole antifungal itraconazole may be cost prohibitive in brand name form; therefore, compounded and generic products are often used as alternatives. Itraconazole blood concentrations have not been studied in clinical patients receiving these formulations. Itraconazole bioassay was performed on serum/plasma from 95 dogs and 20 cats receiving itraconazole (compounded from bulk powder, generic pelletized, or brand name) for systemic mycosis treatment. Mean itraconazole concentration was lower in the compounded group (n = 42) as compared with the generic (n = 40) or brand name (n = 33) groups (0.5 µg/mL versus 8.3 µg/mL and 6.5 µg/mL, respectively; P < .001). No statistical difference was observed between itraconazole concentrations in the generic and brand name groups. Forty animals (95.2%) in the compounded group had subtherapeutic (<1.0 µg/mL) values. All cats in this group (n = 10) had undetectable itraconazole concentrations. Some animals in the generic and brand name groups had subtherapeutic values (12.5 and 12.1%, respectively) or potentially toxic values (>10 µg/mL; 37.5 and 24%, respectively). Compounded itraconazole should be avoided, but generic itraconazole appears to serve as a reasonable alternative to brand name itraconazole. Therapeutic drug monitoring may be beneficial in all cases.

Companion Notes

Comparison of compounded, generic and innovator-formulated itraconazole in dogs and cats

Introduction on the triazole antifungal itraconazole

- commonly used for systemic fungal infections in dogs, cats, and humans

- such as blastomycosis and histoplasmosis

- commercially available innovator-formulated formulations

- capsules

- 100 mg itraconazole coated on spheres

- spheres made of sucrose, maize starch and purified water

- and inactive ingredients including polyethylene glycol

- these facilitate absorption

- drug bioavailability in capsule form is low during fasting

- increases greatly taken with food

- oral solution

- contains cyclodextrin in order to improve bioavailability

(as compared to capsule form)

- variable intestinal absorption is problematic for both products

(capsule and solution-based)

- brand name medication can be cost prohibitive

- capsules typically cost >$1000/month for a 20 kg dog

- with extended treatment duration that’s often >90 days

- FDA-approved human generic capsules cost ~ ¼ the cost of brand name capsules

- nonapproved generic capsules may cost as little as 1/8 that of brand name capsules

- compounded itraconazole discouraged by veterinary specialists

(estimated as low as <$100/month for a 20 kg dog)

- due to perceived treatment failures in dogs

- in a study of 9 healthy beagle dogs

- 1 compounded product produced a very low mean plasma level

- not bioequivalent to brand name itraconazole

- generic itraconazole also not statistically bioequivalent

- it could produce plasma levels similar to the brand name though

- steady state level in dogs and cats reached after 14-21 days after starting oral use

- evaluation at steady state recommended due to unpredictable intestinal absorption

- high-performance liquid chromatography (HPLC) is 1 method of testing levels

- in human medicine:

- therapeutic plasma levels by HPLC should be at least 0.5-1.0 µg/mL

- microbiological assays (bioassay) are typically 3-10-fold higher

(than HPLC)

- in 1 study on bioassay

- suggests levels >17.1 µg/mL are associated with higher risk of toxicity

- in canine medicine:

- the following are positively correlated with itraconazole blood level

- serum alkaline phosphatase activity

- alanine aminotransferase activity

Study design

- study population:

- 95 dogs and 20 cats receiving itraconazole for a systemic mycosis

- compounded from bulk powder, 42 cases

- mean dosage of itraconazole, 8.0 mg/kg/day

- these contained bulk itraconazole powder in any form

- oral suspension, capsule, chewable tablet, etc

- from a wide variety of compounding pharmacies

- generic pelletized, 40 cases

- mean dosage of itraconazole, 6.0 mg/kg/day

- lower than compounded group (P = .013)

- these had to contain pelletized itraconazole inside capsules

- brand name, 33 cases

- mean dosage of itraconazole, 7.4 mg/kg/day

- lower than compounded group (P = .015)

- oral solution and capsules

- procedure:

- itraconazole bioassay performed on serum/plasma from all animals

(MiraVista Diagnostics, Indianapolis, Indiana)

- performed from 12/12-04/14

Results

- mean itraconazole levels

- significantly lower in compounded group than generic or brand name groups

- levels in compounded group: 0.5 ± 1.7 µg/mL

- 40 (95.2%) of the 42 had subtherapeutic (< 1.0 µg/mL) values

- mean dosage of itraconazole in animals receiving compounded form

- in the cats: 12.6 ± 7.2 µg/mL (relatively high)

- all had an undetectable itraconazole concentration

- in the dogs: 6.7 ± 7.2 µg/mL

- levels in generic group: 8.3 ± 5.9 µg/mL

- 12.5% had subtherapeutic (< 1.0 µg/mL) values

- 37.5% had potentially toxic values (< 10 µg/mL)

- 4 cats had received generic itraconazole

- at 3.6, 5.8, 3.2, and 11.4 mg/kg/day

- with respective blood levels at 0.3, 0.3, 0.7 and 17.4

- levels in brand name group: 6.5 ± 5.3 µg/mL

- not significantly different from generic group

- 12.1% had subtherapeutic (< 1.0 µg/mL) values

- 24% had potentially toxic values (< 10 µg/mL)

- 6 cats had received brand name itraconazole

- at dosages of 4.3, 5.0, 4.8, 10.4, 11.3, and 9.2 mg/kg/day

- with respective blood levels at 0.3, 0.6, 1.0, 4.9, 7.7 and 9.7

- itraconazole concentrations and corresponding dosages in generic and brand name groups

- subtherapeutic and equivocal concentrations (0-2.9 µg/mL)

- generic mean dosage: 4.5 ± 1.4 mg/kg/day

- brand name mean dosage: 4.9 ± 0.9 mg/kg/day

- therapeutic concentrations (3.0-10.0 µg/mL)

- generic mean dosage: 6.3 ± 1.5 mg/kg/day

- brand name mean dosage: 8.5 ± 2.6 mg/kg/day

- potentially toxic concentrations (> 10.0 µg/mL)

- generic mean dosage: 6.7 ± 2.6 mg/kg/day

- brand name mean dosage: 7.5 ± 2.3 mg/kg/day

“In this study, we demonstrated very low itraconazole blood concentration in clinical patients receiving compounded itraconazole. Compounding from bulk itraconazole for animal use is currently not permitted under the most recent (2003) Compliance Policy Guide of the FDA….”

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